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Targeting certain lipids, proteins may reduce residual CVD risk
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BOSTON — Targeting lipoprotein(a) and other lipids and proteins known to be associated with CVD may benefit patients who remain at high CVD risk despite LDL lowered to an optimal level, according to a presentation at the Cardiometabolic Health Congress.
Genetically validated targets beyond LDL include Lp(a), apolipoprotein B, triglycerides, ApoC-III, ApoA-I and ANGPTL3, said Sotirios Tsimikas, MD, FACC, FAHA, FSCAI, vice president of global cardiovascular development at Ionis Pharmaceuticals and professor of medicine and director of vascular medicine at the University of California, San Diego School of Medicine.
These targets may be crucial because studies have shown that patients whose LDL levels have been lowered to optimal levels continue to have events, he said.
In IMPROVE-IT, adding ezetimibe to statin therapy conferred a 2% absolute reduction in CV events, but 32.7% of patients assigned ezetimibe plus simvastatin had events over 6 years despite reduction in LDL to a mean of 53 mg/dL, he said.
“That should give you some pause as to why [residual risk] is happening,” Tsimikas said.
In the FOURIER trial, patients assigned evolocumab (Repatha, Amgen) on top of statin therapy achieved a mean LDL of approximately 30 mg/dL, but 12.6% of them had events over 3 years, he said.
“This is why I think we need other ways to reduce cardiovascular risk beyond LDL cholesterol,” Tsimikas said.
Triglyceride levels predict short- and long-term risk in patients with ACS, even after adjustment for conventional risk factors, he said.
Lp(a) also appears to confer elevated risk for CV events, as pooled data from the AIM HIGH, JUPITER and LIPID trials indicated that patients in the highest quartile of Lp(a) level had a 61% increased risk for CV events, despite being on lipid-lowering therapy, according to Tsimikas.
Lp(a) appears to be strongly associated with CHD, aortic valve stenosis, HF, peripheral vascular disease, stroke and chronic kidney disease, he said.
“What we’re finding out is that it’s more of a pro-inflammatory, pro-atherogenic risk factor based on oxidase phospholipids that it carries,” he said.
Few are aware that elevated Lp(a) is about as common as hypertension, as levels greater than 30 mg/dL are considered abnormal, and epidemiological studies suggest that approximately 2 billion people globally exceed that threshold, he said.
Lp(a) is considered a monogenetic driver of risk, and the gene associated with Lp(a) has the strongest link to CAD of any gene, according to Tsimikas.
Most doctors do not measure Lp(a) in their patients, but studies have shown that measuring Lp(a) reclassified nearly 40% of patients deemed intermediate risk by the Reynolds Risk Score, and approximately 15% of patients deemed intermediate risk by the American College of Cardiology/American Heart Association pooled-cohort risk equation, he said.
“This suggests it is helpful at the bedside for trying to fine-tune risk,” he said.
There are no therapies approved to treat Lp(a) specifically, but it is known that niacin, PCSK9 inhibitors, RNA therapeutics, mipomersen (Kynamro, Genzyme/Ionis) and apheresis lower it, according to Tsimikas.
“The Lp(a) hypothesis has never been tested formally,” he said. “All the studies that have to do with Lp(a) and outcomes are secondary, ad hoc or hypothesis-generating analyses. We’ve never had a trial of high Lp(a) randomization to a therapy vs. placebo.”
Also underappreciated is that Lp(a) and oxidized phospholipids seem to rise moderately after statin therapy.
“The question is, is this part of the residual risk that we are seeing in our patients on statin therapy?” Tsimikas asked. “Are we benefiting them by lowering their LDL but then causing detriment by increasing their Lp(a)?”
PSCK9 inhibitors lower Lp(a) by 5 mg/dL to 10 mg/dL, but that is not helpful for patients with very high levels, he said.
Therefore, he said, a therapy specifically designed to lower Lp(a) could be of great benefit.
Ionis and its subsidiary Akcea Therapeutics have developed an antisense agent, IONIS-APO(a)-LRx, that targets ApoA-I, and “the Lp(a) reduction tracks very nice with the ApoA-I reduction.”
In a phase 1 study, the agent produced dose-dependent significant reductions in Lp(a), he said, noting that those assigned a single-ascending dose had a mean reduction of 85% and a maximum reduction of 97%, and those assigned a multiple-ascending dose had a mean reduction of 92% and a maximum reduction of 99%.
“If you get a 90% reduction in Lp(a), you should be able to get almost everybody to normal in any kind of trial that you do, assuming you can give these doses chronically,” he said.
Other agents targeting other potential links to CVD are also in development, he said.
One, volanesorsen (Akcea/Ionis), has been shown to reduce triglycerides and ApoC-III levels in patients with familial chylomicronemia syndrome, and the FDA is considering approving it for those patients, he said.
Loss-of-function mutations of ANGPTL3 are associated with lower levels of LDL and triglycerides and reduced risk for CAD, so there is now a lot of interest in targeting the ANGPTL3 protein, Tsimikas said.
“If you knock down [ANGPTL3], you increase lipoprotein lipase activity, and this can affect triglyceride metabolism,” he said.
An antisense agent (AKCEA-ANGPTL3-LRx, Ionis/Akcea) and a monoclonal antibody (evinacumab, Regeneron) are being developed to target ANGPTL3, he said.
“All the ‘bad guys’ except Lp(a) go down when these are administered,” he said. “This bodes well for cardiovascular event reduction.” – by Erik Swain
References:
Tsimikas S, et al. Lp(a) and promising new targets for intervention. Presented at: Cardiometabolic Health Conference; Oct. 4-7, 2017; Boston.
Viney NJ, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)31009-1.
Disclosure: Tsimikas reports he is an employee of and receives personal fees from Ionis Pharmaceuticals and is named as an inventor on patents held by UCSD related to assessment of atherogenesis, risk prediction and therapy.